Elastase is a serine protease capable of degrading mainly elastin and also connective tissue proteins such as collagen, cartilage, and fibronectin(see: Reilly, C. et al., Biochem. Biophys. Acta., 621: 147-167(1980); Mainardi, C. L. et al., J. Biol. Chem., 255: 5436-5441(1980)). Human leukocyte elastase is stored principally in neutrophils and the stored elastase is released, when neutrophils encounter foreign pathogens or antigens in blood, to degrade them so that body is protected from the harmful factors(see: Weisemann, G. et al., New Engl. J. Med., 303: 27-34(1980)).
However, uncontrolled secretion of elastase which frequently results from aging of the cells or genetic defects may cause non-specific proteolysis and trigger destructive processes associated with various chronic diseases such as rheumatoid arthritis, emphysema, and psoriasis(see: Glinski, W. et al., J. Invest. Dermatol., 75: 481-487(1980); Snider, G. L., Med. Clin. North. Am., 65: 647-666(1981)): Rheumatoid arthritis is an inflammatory disease resulting from an excessive release of elastase which causes abnormal degradation of cartilage at joints of the knee and the finger in human; emphysema is also an inflammatory disease caused by the degradative action of elastase excessively released from neutrophils which have come into the injured site of the lung tissue to prevent intrusion of pathogens from air; and, psoriasis is one of the representative skin diseases caused by elastase, which is characterized by distinct, reddish, slightly raised plaques-with adherent silvery scale.
In medical field, for the treatment of said diseases, strenuous efforts have been made in developing an agent which can effectively suppress the activity of elastase which is released abnormally in excess in the tissues of joint cartilage, lung, and skin. As a consequence, elastase-inhibiting proteins have been isolated from a variety of biological sources such as birds including turkeys or ducks, european leeches, and human skin (see: Schalwijk, J. et al., Br. J. Dermatol., 1512: 181-186(1986); Wlodow, O. et al., J. Biol. Chem., 165: 14791-14796(1990); Hochstrasser, K. et al., Hopps-Seyler's Z. Physiol. Chem., 362: 1369-1375(1981); Seemuller, U. et al., Hopps-Seyler's Z. Physiol. Chem., 361: 1841-1846(1980)), which were found effective for the treatment of said diseases, especially when a medicine containing the protein as an active ingredient was administered directly to the affected parts.
However, the elastase-inhibiting proteins of prior art, except the one isolated from human skin, have had trouble for the use as a medicine, since their specificity for elastase is so low that the activities of other enzymes are possibly inhibited. Moreover, since the said elastase-inhibiting proteins including the one from human skin have an extremely high molecular weight, a problem has been frequently encountered that the proteins can be easily denatured by heat, which decreases their activities rapidly.